An effective vaccine is needed for prevention of HIV-1 transmission. This proposal is directed to identifying, in the SIV-rhesus macaque animal model, correlates of protection against vaginal transmission conferred by prior infection with an attenuated ?-nef strain of SIV. Microarray transcriptional profiling of cervical, vaginal and lymphatic tissues, at times when the extent of protection differs markedly, is proposed as a means to identify correlates of protection in: (i) particular or novel components of innate and adaptive immunity;(ii) a balanced up-regulation of innate and adaptive immune responses without the pro-inflammatory component that recruits CD4 T cells to fuel local expansion and systemic infection;and (iii) mechanisms of protection related to unexpected components of the innate and adaptive response, mechanisms related to the mucosal epithelial response to virus exposure, or wholly novel defenses suggested by the microarrays. These insights can then be harnessed in future work to design an effective vaccine to protect women from HIV-1 acquisition. PUBLIC HEALTH RELEVANCE: An effective vaccine to prevent HIV-1 is urgently needed. In this proposal, transcriptional profiles of cervical, vaginal and lymphatic tissues will be determined in infection with an attenuated ?-nef strain of SIV to identify novel correlates of protection with this vaccine approach.